Tag: FAS

Systemic Lupus Erythematosis, otherwise known as lupus, is an autoimmune disease cause your own immune system attacking various cells and tissues in your body. Lupus patients can suffer from fatigue, joint pain and selling and show a marked increased risk or osteoporosis.

Clinical trials have established that infusions of mesenchymal stem cells (MSCs) can significantly improve the condition of lupus patients, but exactly why these cells help these patients is not completely clear. Certainly suppression of inflammation is probably part of the mechanism by which these cells help lupus patients, but how do these cells improve the bone health of lupus patients?

Songtao Shi and his team at the University of Pennsylvania have used an animal model of lupus to investigate this very question. In their hands, transplanted MSCs improve the function of bone marrow stem cells by providing a source of the FAS protein. FAS stimulates bone marrow stem cell function by means of a multi-step, epigenetic mechanism.

This work by Shi and his colleagues has implications for other cell-based treatment strategies for not only lupus, but other diseases as well.

“When we used transplanted stem cells for these diseases, we didn’t know exactly what they were doing, but saw that they were effective,” said Shi. “Now we’ve seen in a model of lupus that bone-forming mesenchymal stem cell function was rescued by a mechanism that was totally unexpected.”

In earlier work, Shi and his group showed that mesenchymal stem cell infusions can be used to treat various autoimmune diseases in particular animals models. While these were certainly highly desirable results, no one could fully understand why these cells worked as well as they did. Shi began to suspect that some sort of epigenetic mechanism was at work since the infused MSCs seemed to permanently recalibrate the gene expression patterns in cells.

In order to test this possibility, Shi and others found that lupus mice had a malfunctioning FAS protein that prevented their bone marrow MSCs from releasing pro-bone molecules that are integral for bone maintenance and deposition.

A deficiency for the FAS protein prevents bone marrow stem cells from releasing a microRNA called miR-29b. The failure to release miR-29b causes its concentrations to increase inside the cells. miR-29b can down-regulate an enzyme called DNA methyltransferase 1 (Dnmt1), and the buildup of miR-29b inhibits Dnmt1, which causes decreased methylation of the Notch1 promoter and activation of Notch signaling. Methylation of the promoters of genes tends to shut down gene expression, and the lack of methylation of the Notch promoter increases Notch gene expression, activating Notch signaling. Unfortunately, increased Notch signaling impaired the differentiation of bone marrow stem cells into bone-making cells. Transplantation of MSCs brings FAS protein to the bone marrow stem cells by means of exosomes secreted by the MSCs. The FAS protein in the MSC-provided exosomes reduce intracellular levels of miR-29b, which leads to higher levels of Dnmt1. Dnmt1 methylates the Notch1 promoter, thus shutting down the expression of the Notch gene, and restoring bone-specific differentiation.

Shi and others are presently investigating if this FAS-dependent process is also at work in other autoimmune diseases. If so, then stem cell treatments might convey similar bone-specific benefits.